The oral absorption and bioavailability of drug molecules, particularly poorly water-soluble (e.g., hydrophobic and/or lipophilic) drug molecules is a significant challenge for the pharmaceutical industry. Bioavailability of a drug is important as it affects the drug's adsorption into the body, for example, across the gastrointestinal (GI) tract. One strategy involves reducing the particle size of drug crystals to form micron or sub-micron sized drug particles, the latter being termed nanocrystals. By reducing the particle size of the drug the surface area is increased which results in an increased dissolution rate and therefore improved oral absorption. For example, the delivery of active pharmaceutical ingredients (APIs), and particularly those with low aqueous solubility, by both the oral and parenteral route has been achieved by formulating APIs as micron and sub-micron sized particles suspended in water or oil based formulations. Formulations intended for the oral route are usually suspensions of the API in water. Formulations intended for parenteral use are usually formulated as either aqueous suspensions or oil based suspensions.
Such formulations are technically challenging as illustrated in International Journal of Current Pharmaceutical Research, Vol 2, Issue 3, 2010, which noted that formulations for both aqueous and oil based formulations are multi-component and typically require flocculating or suspending agents, wetting agents, stabilizers, solvent systems and preservatives. Such formulations often suffer from lack of chemical and physical stability (i.e., control of settling and caking). For example particle interaction and aggregation increases as particle size decreases which can lead to agglomeration of the particles, settling of suspended particles and poor physical stability. Ostwald ripening, where small particles dissolve and re-crystallise to form larger particles can also be an issue. To overcome these problems nanocrystals are usually generated in the presence of stabilisers, for example surfactants or polymers, which stabilise the nanocrystals by creating a steric barrier. The nanocrystals may then be recovered from the aqueous suspension for incorporation into oral dosage forms such as capsules or tablets. Nanocrystals may be produced by breaking down larger crystals. Preferably, the nanocrystals are produced by milling or ablation.
One approach to overcoming these challenges is to modify the surface of particles in both aqueous and non-aqueous media. U.S. Pat. No. 6,086,376 discloses the production of an aerosol formulation where particles are surface modified using membrane forming phospholipids and a surfactant, and subsequently these particles are dispersed in non-aqueous fluorinated propellent. Such particles may also be suspended in water-in-oil and oil-in-water emulsions. However, these are complicated systems requiring surface modification of the particles to ensure stability of the drug and the emulsion system.
Another approach described in WO01/21154 is to surface modify sub-micron and micron sized particles of water insoluble biologically active substances from a carrier system comprising a non-aqueous medium, one or more surfactant(s) and optionally a hydrophilic component that self disperses on exposure to an aqueous environment. Three methods are used to produce the compositions of surface modified particles. Method I utilises a particle size reduction process to form aqueous suspensions of surface modified particles. An aqueous premix of the API and the surfactant system is prepared and particle sized reduced. A suspension of surface modified small particles ranging from 0.01 to 10 micron is obtained. This suspension is subjected to a drying process (spray drying or lyophilisation) to yield a dry powder of particles which is then mixed or homogenised with the non-aqueous media and optionally additional components of the surfactant system. Method II uses an anti-solvent precipitated surface stabilised API in a non-aqueous carrier. In this process the surfactant system is dissolved with the API in a solvent and then precipitated with an anti-solvent. Particles are then dried as in method I and combined with a non-aqueous medium. In a third embodiment the API is particle size reduced in the presence of the surfactant system and the non-aqueous medium. In all three cases the methods involve the combination of API with a surfactant system and the non-aqueous media. However, WO 01/21154 is entirely speculative as to the physical stability of the formulations described therein. Moreover, preparation of the formulations described in the art involves complicated manufacturing steps.
Alternative methods for formulating the capsules may be used. The drug crystals can be milled in a non-aqueous liquid (lipid or non-lipid) medium, rather than an aqueous medium, to create a suspension of nanocrystals in the non-aqueous liquid.